**9. Other molecules**

### **9.1 Rigerimod**

Rigerimod is a spliceosomal peptide recognized by lupus CD4+ T cells [105]. In a phase 2 trial, rigerimod was safe and efficient in the achievement of SRI-4 response at W12, in the group receiving 200 μg subcutaneously every 4 weeks (61.9% versus 38.6 in the placebo group (p = 0.016)).

#### **9.2 Abetimus**

Abetimus sodium is a tetrameric oligonucleotide conjugate reducing antidoublestranded DNA [106]. Due to the anti-ds DNA antibodies' role in the pathogenesis of LN, abetimus was evaluated in phase 2 and phase 3 trials in a cohort of patients at high risk of nephritic flare [107, 108]. The primary endpoint of prolongation of time to renal flare was not met, despite the reduction of anti-ds DNA.

*Targeted Therapies for Systemic Lupus Erythematosus (SLE): A Critical Appraisal DOI: http://dx.doi.org/10.5772/intechopen.105811*

#### **9.3 SM101**

SM1O1 is a human soluble non-glycosylated version of the Fcγ receptor IIB, inhibiting the binding of immune complexes to cell-standing Fcg receptors [109] that has already been evaluated in a phase I/II trial in patients with immune thrombocytopenia with a good safety profile and clinical response [110]. In a phase 2a trial in 51 patients with SLE, it proved to be well tolerated and efficient, mostly in terms of improvement in arthritis and in skin rash (present in 75% and 50% patients, respectively) assessed by the BILAG scale [109].

## **10. Targeting B-cell intracellular functions**

#### **10.1 Targeting Bruton's tyrosine kinases**

Bruton's tyrosine kinase (BTK) is implicated in both B-cell and Fcγ-R-mediated myeloid cell activation, playing a crucial role in B-cell survival and proliferation. BTK represents a treatment target in patients with hematological malignancies [111]. BI-BTK-1, an irreversible BTK inhibitor, ameliorated multiple pathological endpoints associated with kidney disease in two distinct murine models of spontaneous lupus nephritis [112]. Fenebrutinib (GDC-0853) a noncovalent, oral, selective BTK inhibitor was evaluated in a phase 2 trial [113], in patients with active SLE; although februtinib significantly reduced levels of CD19-positive B cells, anti- double-stranded DNA autoantibodies, and a BTK-dependent RNA signature expressed in plasmablasts compared with placebo, it failed to achieve SRI-4 response at W48. Ibrutinib, another BTK inhibitor used in B-cell malignancies, resulted in reduced levels of autoantibodies and less severe nephritis in SLE murine models [114].

#### **10.2 Proteasome inhibitors**

Long-lived plasma cells are resistant to conventional and B-cell depleting strategies and play a critical role in the maintenance of autoimmunity in patients with refractory SLE [115]. Bortezomib, a proteasome inhibitor used in multiple myeloma, has successfully been used in patients with multiple refractory autoimmune diseases including ITP [116] and warm antibody hemolytic anemia [117]. In 12 patients with refractory SLE, it not only depleted plasma cells but also ameliorated clinical manifestations [118]. These encouraging results were not confirmed in a multicenter RCT including 14 patients: there were neither serological nor statistically significant clinical effects in the bortezomib group [119]. However, in patients with LN, it seemed to reduce proteinuria, improve renal function, and decrease autoantibodies, with mild adverse events [120].

#### **10.3 Eculizumab**

Eculizumab is a fully humanized IgG2/IgG4 monoclonal antibody directed at C5, preventing the formation of the terminal complement complex, used in atypical hemolytic uraemic syndrome (aHUS) and paroxysomal nocturnal hemoglobinuria (PNH) [121]. Eculizumab has been successfully used in patients with secondary TMA due to SLE and/or APS that are non-responsive to standard of care [122].
